KUAKINI COBRE CONTRIBUTIONS FROM LONG-LIVED OKINAWA PREFECTURE: THE FIRST BLUE ZONE

Abstract The Okinawa-Hawaii connection has a long history. The first group of immigrants to Hawaii from Okinawa arrived in 1899, and descendants of these immigrants make up approximately 20% of the Kuakini Honolulu Heart Program (HHP) cohort. Research in Okinawa, and among the Okinawan community in Hawaii, has provided many insights into the subtle differences in lifestyle and genetics among these populations. In order to gain further insight into the lifestyle and genetic factors associated with healthy aging and longevity, the Kuakini COBRE has built a strong collaborative team of researchers from Okinawa and initiated a number of research projects, as well as cross-Pacific training opportunities for COBRE junior investigators (Research Project Leaders). This presentation will outline new insights into healthy aging and longevity that have been discovered through this collaborative relationship. Our findings highlight the intricate relationship between FOXO3 and telomere length change with age, and include the first validated longevity gene variant that shows an association with negligible loss of telomere length with age in humans. This finding reveals that reduced telomere attrition with age may be a key mechanism for the longevity-promoting effect of the FOXO3 genotype. This presentation will also discuss sex differences that play a role in how, and under what conditions, FOXO3 exerts its role in healthy aging. Finally, future collaborative projects involving mitochondrial health and aging will be introduced.


KUAKINI HHP CENTER FOR TRANSLATIONAL RESEARCH ON AGING: LATEST FINDINGS FROM MODEL ORGANISMS TO HUMANS
Chair: Bradley Willcox Co-Chair: Richard Allsopp Discussant: Peter Martin Kuakini Medical Center (Kuakini) was funded by NIH in late 2019 to create an interdisciplinary Hawai'i-based, Center of Biomedical Research Excellence (COBRE), for translational research on aging.This Center is building upon Kuakini's five-decades of prior NIH-funded research.These resources include clinical data from the 58-year ongoing Kuakini Honolulu Heart Program (HHP), Honolulu-Asia Aging Study, HHP Offspring Study and a large biorepository with over 500,000 biological samples.The Center's overarching aim is to increase infrastructure for collaborative aging research in Hawaii.The first step is to grow the Center's faculty by hiring and mentoring research project leaders (RPLs) from diverse disciplines to become independent, R01-funded, investigators on aging.Our first RPL has graduated after obtaining R01-funded status.His project utilizes novel CRISPR methods to i) improve the safety and efficacy of delivering potentially therapeutic genes (such as FOXO3) to the mouse genome, and ii) test whether temporal enhancement of FOXO3 expression improves healthy aging in this mouse model -both key steps for potential translation to human clinical therapies.This work will be highlighted in the Program Overview session followed by current RPL findings.These findings include novel findings on a potential relation between FOXO3 genotype and stroke dynamics in elderly Japanese-American males; venous congestion in the brain and its potential impact on cognitive function; new findings on the Okinawan longevity phenomenon, among other interesting findings related to healthy aging.Supported by NIGMS 5P20GM125526 and NIA R01AG027060.
subtle differences in lifestyle and genetics among these populations.In order to gain further insight into the lifestyle and genetic factors associated with healthy aging and longevity, the Kuakini COBRE has built a strong collaborative team of researchers from Okinawa and initiated a number of research projects, as well as cross-Pacific training opportunities for COBRE junior investigators (Research Project Leaders).This presentation will outline new insights into healthy aging and longevity that have been discovered through this collaborative relationship.Our findings highlight the intricate relationship between FOXO3 and telomere length change with age, and include the first validated longevity gene variant that shows an association with negligible loss of telomere length with age in humans.This finding reveals that reduced telomere attrition with age may be a key mechanism for the longevity-promoting effect of the FOXO3 genotype.This presentation will also discuss sex differences that play a role in how, and under what conditions, FOXO3 exerts its role in healthy aging.Finally, future collaborative projects involving mitochondrial health and aging will be introduced.

FOXO3 LONGEVITY GENOTYPE AND CEREBROVASCULAR DISEASE Kazuma Nakagawa, Kuakini Medical Center, Honolulu, Hawaii, United States
The influence of the FOXO3-longevity associated genotype on cerebrovascular disease (CVD) is little studied.There are reports of a protective effect against stroke mortality in some populations.But these findings have not been widely replicated, nor have potential mechanisms been identified.This presentation will present recent, novel insights on the relation of FOXO3 genotype to CVD.We studied a cohort of over 800 American men of Japanese ancestry from the Kuakini Honolulu Heart Program (KHHP) and Kuakini Honolulu-Asia Aging Study (KHAAS).This populationbased dataset included brain autopsy data and age-adjusted prevalence of various types of CVD, including intracerebral hemorrhage (ICH) and cerebral microinfarcts (CMI).Logistic regression models, adjusted for age at death, cardiovascular risk factors, FOXO3 and APOE-ε4 genotypes, among other risk factors were utilized to determine the predictors of both outcomes.FOXO3 genotype did not directly modify risk for ICH or CMI.However, the FOXO3 longevity genotype had significant interaction (protective) effects against hypertension-associated ICH and CMI.These data suggest that the longevity-associated FOXO3 G-allele mitigates the impact of hypertension on the risk of ICH and CMI.Further research is needed in other populations.
Abstract citation ID: igad104.0779Ferdinand Hui, Kuakini Medical Center, Honolulu, Hawaii, United States Cerebral venous congestion (CVC) has been identified as a hypothetic cause of cognitive impairment.Prior work has estimated that 15-30% of the population may have jugular venous narrowing, a potential cause of CVC, based on reviews of CT angiography (CTA) performed at a large academic medical center.However, few comprehensive studies exist.Therefore, for the current work, we reviewed fifty CTAs that were obtained for ischemic stroke triage and thrombectomy planning at a comprehensive stroke center in Hawaii (Queens Hospital, Honolulu HI).These brain CTAs were analyzed for arterial and venous variants and other abnormalities that might place the patient at increased risk for arterial injury and/or venous congestion, both of which may result in cognitive decline.The CTAs were analyzed retrospectively for every known level of venous and arterial stenosis, and CVC-associated pre-morbid symptoms were analyzed.Preliminary data support the hypothesis that venous anatomical anomalies may be a risk factor for cognitive impairment.CVC may be an under-diagnosed contributor to cognitive impairment, particularly in older patients.

INTERDISCIPLINARY APPROACHES TO EPIDEMIOLOGY AND PREVENTION OF FALLS IN OLDER ADULTS
Chair: Wenjun Li Discussant: Wenjun Li Prevention of falls is important to independent living and good health in older age.This symposium brings together five interdisciplinary studies on falls among community-dwelling older adults.The first presentation examines the relationship between multisite pain and fear of falling among older adults with dementia.The second discusses the differential effects of anxiety on indoor vs. outdoor falls.The cohort study found that anxiety was associated with higher rate of indoor but not outdoor falls.The third investigates racial differences in association of accelerometer measured physical activity with indoor and outdoor falls.The study found that a 30-minutes increase in moderate-to-vigorous intensity physical activity was associated with 25% lower rate of indoor falls and 42% higher rate of outdoor falls among non-White but not White participants, an interesting example of effect modification by race and location of falls.The fourth reports findings of a cross-sectional survey of older adults in Thailand which observed high prevalence of falls, and substantial differences in fear of falling, daily activities and quality of life between fallers and non-fallers, and between persons with and without fear of falling.The fifth reports rural-urban differences in circumstances and correlates of falls from the same study in Thailand.The study found higher fall rates, higher level of fear of falling and worse general health in urban than rural residents, highlighting the need for considering urbanrural differences in falls prevention.Together, these studies demonstrate the complexity and promises of interdisciplinary approaches to falls research.